Project Summary/Abstract: A long-standing question in biology is how cells respond to the myriad of signals around them generating a specific response. A paradigmatic example is found during mammalian brain development. Neurons born from progenitor cells located in discrete niches move out and migrate, sometimes long distances, to reach their final position. A variety of guidance cues pilot these neurons from their birthplace to their final location, where they stop, mature and integrate into the existing cellular network. Signaling pathways are activated in response to guidance cues or chemotactic signals and once the information is transduced, the original signaling pathway must be downregulated. Inappropriate regulation of signaling pathways causes neurons to mismigrate, lose responsiveness to new signals and/or sustain the original signaling response, causing harm or death to the cell. The overarching goal of the present project is to understand the mechanisms by which ubiquitin- dependent degradation of specific substrate proteins regulates hippocampal development and adult neurogenesis. The ubiquitin-proteasome system is one of the most efficient methods to tightly control signaling pathways, by targeting key signaling components for degradation. This system relies on the coordinated action of 3 enzymes, named E1, E2 and E3 ligases to conjugate the small protein ubiquitin to specific signaling effectors that will be targeted for degradation. The PI previously identified the E3 Cullin-5 RING ligase (CRL5) as a crucial regulator of neuron migration and cell position in several areas of the nervous system. However, the role of CRL5 in the developing and adult hippocampus has never been investigated. Our preliminary data identified novel CRL5-regulated signaling effectors during hippocampal development. Also, we show that CRL5 regulates the position of pyramidal neurons in the CA and neural progenitors and granule cells in the dentate gyrus. Moreover, depletion of CRL5 activity disrupts dendritogenesis and axogenesis of hippocampal neurons. Finally, our preliminary data also indicates that CRL5 regulates adult neurogenesis in the dentate gyrus. The three proposed specific aims will significantly advance our understanding of the role of CRL5 in the developing and adult hippocampus by answering: 1) Which signaling pathways are regulated by CRL5 in the developing hippocampus and in the adult?; 2) What is the role of the ARLA4C signaling in the hippocampus?; 3) How does CRL5 regulate migration and dendrite and axon formation in hippocampal cells?; and 4) How does CRL5 influence adult neurogenesis? The successful completion of the project will provide the first molecular portrait of the hippocampal signaling pathways regulated by CRL5, reveal the biological role of CRL5 in the hippocampus, and identify CRL5 as a novel regulator of adult neurogenesis in the hippocampus.